Breast cancer survivors currently comprise the largest group of cancer survivors in the United States at 2.9 million women. One of the most common and problematic phenomena experienced by breast cancer survivors is changes in cognitive function or cognitive decline, defined as a decrease or loss in one or more domains of cognitive function including attention, learning, memory, psychomotor speed, mental flexibility, executive function, and visuospatial ability. While multiple factors potentially predict poorer cognitive function in women with and receiving treatment for breast cancer, we hypothesize that disease-related factors of breast cancer may be a major contributor to cognitive decline. Our overall goal is to gain a better understanding of the biological foundations of cancer- and treatment-related cognitive decline. The specific aims of the proposed research are: 1) To investigate the relationship between clinicopathologic tumor features of breast cancer and cognitive function in women with breast cancer, 2) To explore DNA variation in genes used to clinically evaluate the biology of breast cancer for association with susceptibility to or protectin from cognitive decline in women with breast cancer, and 3) To explore interactions between clinicopathologic tumor features of breast cancer and DNA variation in genes used to clinically evaluate the biology of breast cancer on cognitive function. Using biospecimens and cognitive function data collected from a large, ongoing longitudinal study, the Cognitive Impairment Related to Anastrozole Use in Women Study (R01CA107408), the proposed study will focus on postmenopausal women with early stage breast cancer receiving various chemotherapy and/or hormonal therapy treatment regimens in comparison to healthy age- and education-matched women. Regression modeling, candidate gene association, and moderation analyses (statistical interactions) will be used to explore cognitive function prior to and over time following the initiation of adjuvant chemotherapy and/or hormonal therapy. The findings from this preliminary study will lay the foundation for a line of research to identify clinically relevant biomarkers and novel therapies for survivors of breast cancer experiencing cognitive decline.